The gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) of pituitary origin, and chorionic gonadotropin (hCG, eCG) of placental origin, along with thyroid-stimulating hormone (TSH) constitute a family of glycoprotein hormones. Their isolation, characterization, and biological functions have been the subject of numerous reports. [Licht et al., Recent Prog. Horm. Res., 33:169 (1977); Vaitukaitis et al., Recent Prog. Horm. Res., 32:289 (1976); Ward et al., Recent Prog. Horm. Res., 29:533 (1973); Papkoff et al., Recent Prog. Horm. Res., 29:563 (1973); Canfield et al., Recent Prog. Horm. Res., 27:121 (1971); Pierce et al., Recent Prog. Horm. Res., 27:165 (1971); Ryan et al., Recent Prog. Horm. Res., 26:105 (1970)].
Human glycoprotein hormones (TSH, LH, FSH and hCG) are heterodimers consisting of a hormone specific Beta-subunit and a common .alpha.-subunit, [Pierce, and Parsons, Ann. Rev. Biochem, 50, 465, (1981)]. The intact dimer may be necessary for full biological activity; however, data on the gonadotropic hormones LH and hCG indicate that both the Alpha and Beta subunits interact with the receptor [Ji and Ji, Proc. Natl. Acad. Sci. U.S.A., 78:5465-5469 (1981); Ascoli and Segaloff, J. Biol. Chem., 261:3807-3815 (1986); Moudgal and Li, Proc. Natl. Acad. Sci. U.S.A., 79:2500-2503 (1982); Grasso and Crisp, Endocrinology, 116:319-327 (1985); and Armstrong et al., Biochemical Actions of Hormones, 13:91-128 (1986).
To understand the extent to which the particular subunits contribute to the activity of the intact dimer, a need exists to isolate and characterize the subset of peptides within the subunits, including .alpha.-subunit peptides, which are responsible for the range of biological activities associated with human glycoprotein hormones. Lower molecular weight oligopeptides corresponding to a subunit sequence would be expected to be more readily obtainable, less expensive and exhibit a narrower profile of biological activity than glycoprotein hormones themselves, thus increasing their potential usefulness as therapeutic or diagnostic agents.
One particular human glycoprotein hormone of interest is TSH. The structure and function of TSH are of interest in part due to the hormone's role in thyroid disorders. One such disorder is Graves' disease, an autoimmune disease which occurs most often in women and involves over production of thyroxin by the thyroid.
Graves' disease is characterized by the presence of immunoglobulins (autoantibodies) that inhibit the binding of TSH to its receptor (thyrotropin binding inhibiting immunoglobulin, TBII) and increase adenylate cyclase activity (thyroid stimulating immunoglobulin, TSI or TRAb) in thyroid follicular cells [Volpe, The Thyroid: A Fundamental and Clinical Text, p. 747 (5th ed. 1986)]. The interaction between TSI and TSH receptor has been carefully studied [Smith and Buckland, Receptors, Antibodies, and Disease CIBA Foundation Symposium, p. 114 (1982); Fahraeus-Van Ree and Farid, Clin. Res., 31:679A (1983); Davies and Platzer, Clin. Endocrinol., 19:427 (1983)] and current evidence, suggests that the thyrotropin receptor itself is the antigen [Smith and Buckland, supra]. However, the specific binding site remains unknown.
Individuals affected with Graves' disease exhibit exophthalomos, enlarged pulsating thyroid gland, marked acceleration of the heart rate, a tendency to profuse sweats, nervous symptoms, psychic disturbances, emaciation, increased metabolic rate, and pretibial myxedma. Recognized treatment of Graves' disease involves inactivation of the thyroid gland with radioactive iodine, surgical removal of the gland or treatment with certain antithyroid drugs such as propylthiouracil. While present treatments can alleviate the metabolic disorders, they do not prevent continued exophthalomos and pretribial myxedma. The inability to arrest these manifestations may, in part, be due to the failure of current treatments to inhibit binding of long-acting thyroid stimulator (TSI) to cells in the orbit of the eye and skin.
Therefore, there is a need to study and obtain synthetic .alpha.-subunit peptides of human glycoprotein hormones or analogues thereof which can inhibit TSH binding to human thyroid membrane; inhibit TSH mediated cAMP generation; and also block the action of TSI and block the binding of LH and hCG to their receptors.